Therefore, it was concluded by Santos et. To test our method on Santos et al.
Biochemists don't traditionally have a strong background (or any in some cases) in math. I think Cornish-Bowden's book fills a niche for first and second year. Some teachers of biochemistry think it positively beneficial for students to struggle with difficult mathematics. I do not number myself among these people.
The model is shown below. LRCs calculated from experimental data and experimentally observed pERK kinetics are also shown in this panel for comparison. Model fits represent average of an ensemble of one thousand models fitted to sets of parameters sampled by the variable weight ABC-SMC algorithm. Error bars represent standard error.
Error bars are not visible due to having negligible standard error. The above model Eq. Firstly, unlike in the previous case Eq. This simplification step is avoided to reflect the biological reality that RAF is activated by the RAS proteins which are activated by EGF and NGF via a series of biochemical interactions involving the receptor and adaptor proteins. Secondly, the model in Eq.
Binary variables b e and b n were used to characterize interactions which occur selectively in response to EGF and NGF respectively Fig. The resulting model has twenty four unknown parameters. Fitting such a parameter rich model using such a small number of data points will almost certainly run into model identification problems. Additional data was incorporated in the inference process.
This provides us six additional data points, i. The means of the prior distributions of all model parameters except those of the gamma functions kd egf , kd ngf were set to 2, those of the gamma function parameters kd egf , kd ngf were set to 0. The standard deviations of all priors were set to 2. The inferred parameters were then used to predict different kinetic and steady state pathway behaviours which were not used for model calibration.
Experimental data are shown in the left sub-panels and the model simulations are shown in the right sub-panels. The left and right sub-panels show experimental data and model simulation respectively. Model simulations represent average of an ensemble of one thousand models fitted to different sets of parameters sampled by the variable weight ABC-SMC algorithm. The simulation results partially agreed with the experimentally observed behaviour Fig.
While these general trends were also observed in experimental data obtained from 15 and also shown in Fig. In both cases, the differences between the experimental data and model simulation occur before the application of growth factor neutralizing antibodies.
Therefore, it is unlikely that the difference is caused by error in simulating the effect of the neutralizing factors. A closer look at the two sets of experimentally measured phospho- ERK levels, one without the neutralizers and was used for model calibration Fig. Therefore, in this case, the apparent differences in experimental data and model simulation can be attributed to these factors. Similar sigmoidal relationship between ligand concentrations and active-ERK levels at five minutes after stimulation were experimentally observed in PC12 cells data obtained from 31 , also shown in Fig.
An ensemble of one thousand models fitted to different sets of parameters sampled by the VW-ABC-SMC algorithm were used to calculate mean response solid red lines in panel A and confidence intervals dashed red lines in panel A. The empirical distributions the blue lines in panel B of the simulated pERK levels are shown in blow. Individual Gaussian components that make up the empirical distributions are shown in red and green.
The peak of the individual components are marked using dots of the respective colour. The inferred parameters were used to simulate steady state response of aERK to different doses of NGF at a single cell level. To do so, each sampled set of parameter values were assumed to represent a single cell, thereby, the ensemble of all sampled parameter sets represents a cell population.
To see if the same is true for the simulated aERK levels, we fitted one or two Gaussian probability density functions to each of the aERK distributions depending on whichever produced the minimum fitting SSQ error. In all cases, two Gaussian Distributions provided better fits than a single Gaussian distribution, suggesting that, in our simulations, aERK has bimodal distribution at all levels 0. By that time, the ERK pathway is known to be influence by transcriptional events which are not accounted for in our model 32 , 33 , This might cause some differences between the dose responses of the model and the real ERK pathway.
I proposed a method that can be used to calibrate ODE models to SSPR data without exclusively simulating the perturbation experiments during the calibration process. This has several benefits beyond reducing computational cost.
For instance, the mechanism of action or the exact targets of biochemical inhibitors are often either not known or not straightforward to incorporate in a model without significantly increasing the model complexity. Therefore, the data produced by the perturbation experiments where such inhibitors are used are not useful for fitting ODE models in the traditional way. The proposed approach does not require detailed knowledge of the perturbation experiments, thereby expanding the periphery of usable data for fitting ODE models.
It can also be used in any existing parameter fitting algorithm to speed up the overall calibration process when using SSPR data. The models fitted using this method were shown to be able to largely reproduce STN behavior both at population and single cell level. However, this approach of model fitting is not without its caveats. Since each of these interactions are formulated using kinetic equations that usually have more than one parameters, in almost all cases there are more parameters to fit than the number available LRCs. This becomes even more of an issue for large networks which have many interactions, each of which is formulated using kinetic equations that may have several parameters.
In such cases the difference between the number of parameters to fit and the number of available LRCs become even more apparent. Model complexity also plays a role in parameter identifiability. Mathematical models containing detailed equations for various intermediate stages of biochemical interactions are parameter rich and therefore are not easy to calibrate using LRCs. There are various ways of determining which of the model parameters are identifiable, sensitivity analysis 2 and Fisher Information Matrix 35 are some of the popular options.
A common way 2 of circumventing the parameter identifiability issue is to first determine which parameters are not identifiable, assign these parameters reasonable fixed values, and then infer the values of the rest of the parameters from data. Further information about parameter identifiability issues and potential remedies are described in detail by Raue et al. A more straightforward way of improving parameter identifiability is to following various ligand stimulation. The behavior of biochemical networks varies depending on the dose and type of ligand stimulations, and so do the LRCs of the systems.
The upside of performing perturbation experiments in multiple conditions is that the resulting data is more informative than data from only one condition, but downside is the increased experimental burden. Another potential weakness of the proposed method also stems from its inherent reliance on the LRCs.
The accuracy of the estimated LRCs depend on many factors ranging from noise, numbers and types of perturbation experiments, number of replicate experiments in the SSPR data, to the nature of the MRA based algorithms used to estimate LRCs.
There are currently no rule of thumb for either designing optimal perturbation experiments to produce the most informative SSPR data, or identifying an algorithm which will produce the most accurate estimates of LRCs from an SSPR dataset. Designing optimal experimental protocols and computational algorithms to obtain the most accurate estimate of LRCs is a matter of ongoing research. Aldridge, B. Physicochemical modelling of cell signalling pathways.
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